Prospective associations of leucocyte subtypes and obesity with the risk of developing cutaneous malignant melanoma in the UK Biobank cohort

Background Obesity is associated with chronic low-grade inflammation, which is linked to cancer development. Abdominal obesity (a body mass index, ABSI), however, has unusually been associated inversely with cutaneous malignant melanoma (CMM), while general obesity (body mass index, BMI) is associated positively. Leucocytes participate in inflammation and are higher in obesity, but prospective associations of leucocytes with cutaneous malignant melanoma are unclear. Methods We examined the prospective associations of neutrophil, lymphocyte, and monocyte counts (each individually), as well as the prospective associations of ABSI and BMI, with cutaneous malignant melanoma in UK Biobank. We used multivariable Cox proportional hazards models and explored heterogeneity according to sex, menopausal status, age (≥ 50 years at recruitment), smoking status, ABSI (dichotomised at the median: ≥73.5 women; ≥79.8 men), BMI (normal weight, overweight, obese), and time to diagnosis. Results During a mean follow-up of 10.2 years, 2174 CMM cases were ascertained in 398,450 participants. There was little evidence for associations with neutrophil or lymphocyte counts. Monocyte count, however, was associated inversely in participants overall (HR = 0.928; 95%CI: 0.888–0.971; per one standard deviation increase; SD = 0.144*109/L women; SD = 0.169*109/L men), specifically in older participants (HR = 0.906; 95%CI: 0.862–0.951), and more clearly in participants with low ABSI (HR = 0.880; 95%CI: 0.824–0.939), or with BMI ≥ 25 kg/m2 (HR = 0.895; 95%CI: 0.837–0.958 for overweight; HR = 0.923; 95%CI: 0.848–1.005 for obese). ABSI was associated inversely in pre-menopausal women (HR = 0.810; 95%CI: 0.702–0.935; SD = 4.95) and men (HR = 0.925; 95%CI: 0.867–0.986; SD = 4.11). BMI was associated positively in men (HR = 1.148; 95%CI: 1.078–1.222; SD = 4.04 kg/m2). There was little evidence for heterogeneity according to smoking status. The associations with monocyte count and BMI were retained to at least 8 years prior to diagnosis, but the association with ABSI was observed up to 4 years prior to diagnosis and not for longer follow-up time. Conclusions Monocyte count is associated prospectively inversely with the risk of developing CMM in older individuals, while BMI is associated positively in men, suggesting a mechanistic involvement of factors related to monocytes and subcutaneous adipose tissue in melanoma development. An inverse association with ABSI closer to diagnosis may reflect reverse causality or glucocorticoid resistance. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-024-12344-0.

Leucocytes, obesity, and melanoma in UK Biobank Christakoudi et al. 2023 S3 Supplementary Table S1 Rationale for selection of candidate covariates

Height
To remove residual correlations for allometric anthropometric indices, as discussed in Supplementary Methods of [13].

HRT
Higher use in post and peri-menopausal women, which have higher BMI and ABSI [12].
Weight change Would reflect different BMI trajectories.
Lower risk for weight loss in men [70].

Alcohol
Alterations in relative blood cell counts, with a shift towards a memory T cell phenotype, as well as an inhibition of the cytoskeleton reorganisation of monocytes [71].
Positive association in men not in women [72].
Physical activity Lower leucocyte counts and inflammatory markers with physical activity [73].
Positive associations in cohort studies, potentially related to UV exposure [74].

Socio-economic position
Higher risk of abdominal obesity for low SEP, as a potential source of chronic stress [63], but also modifications of monocyte function [75].
Higher risk for higher income [76].

Diabetes
Associated with abdominal obesity as part of the metabolic syndrome.
Higher risk due to phototoxicity of antidiabetic drugs [77].

Lipid-lowering drugs
May affect leucocyte function due to antiinflammatory properties, as have been associated with lower C-reactive protein [78].
Higher risk with use of lipophilic statins [79].

Antihypertensive drugs
Use would be associated with abdominal obesity, as obesity and hypertension are both are part of the metabolic syndrome.

NSAIDs
May affect leucocyte function due to antiinflammatory properties.
If inflammation is relevant, may contribute to lower risk, but may also contribute to higher risk due to phototoxicity [77].

Antiaggregant/ anticoagulants
Could affect leucocyte function because platelets are involved in immune inflammation [80].
Lower risk with aspirin use in individuals with uncontrolled hypertension [81].

Skin & Hair
The melanocortin pathway, which is relevant to melanoma, is also involved in energy homeostasis [82] and defects in proopiomelanocortin (POMC) synthesis have been associated with red hair, as well as severe obesity [83].
Higher risk for fair hair and white skin [84].

Supplementary Material
Leucocytes, obesity, and melanoma in UK Biobank Christakoudi et  Major risk factor [84], although no strong evidence for association with moderate/responsible solarium use [85].

Sun protection
Could be related indirectly to obesity and inflammation due to different behavioural patterns in individuals with different SEP.
Higher risk before 1980s and no evidence for protection [86].

Fasting time & Time of blood collection
Lymphocyte count decreases while neutrophil count increases after food intake [87].Leucocyte counts are subject to diurnal variation, with higher levels towards the evening [88].
May improve precision of risk estimates, as a way of standardising the conditions of blood collection for leucocyte counts (time of day and fasting time).

Table S3 Characteristics of study participants
-a body shape index; BMI -body mass index; CMM -cutaneous malignant melanoma; HRT -hormone replacement therapy; NSAIDs -non-steroidal anti-inflammatory drugs; SEPsocio-economic position.A directed acyclic graph of the relationships of candidate covariates with the exposures and the outcome is shown in Supplementary Figure S1.Pairwise associations of candidate covariates with the exposure and the outcome are shown in SupplementaryTable S2 (separate file).S5 Supplementary